Citations

Wormlike micellar (WM) fluids exhibit a self-assembly property and viscoelastic behavior which make them a promising material for representing biological fluids, ultrasoft tissue phantoms and drug delivery carriers. Although WM biochemistry has been investigated, the mechanical properties have been rarely discussed because of the complexity of soft matter systems. Here, we demonstrate that optical coherence elastography (OCE) is capable of measuring Rayleigh wave of micellar fluids. Three solutions with concentrations of 100, 200, 300 and 400 mM, were considered in the study. Ultrasound excitation to produce Rayleigh waves was accomplished using 7.5 MHz burst excitation signals of length 4.0 ms repeated at a rate of 19 Hz. The optical coherence tomography (OCT) acquisition was set to 50 lateral positions and 4000 A-scans for each lateral position at a 76 kHz scan rate for total acquisition time of 52.6 ms. Ultrasound-based shear wave elastography, implemented on a Verasonics system, was used to obtain group and phase velocity of the shear wave in all micellar fluids as reference. Our research results demonstrated that Rayleigh wave in micellar fluids can be evaluated by OCE and mechanical properties like Young’s modulus can be assessed. A wide of concentration ranges of WM fluids would provide a more realistic model to mimic biological fluids and tissues.

Patients with chronic kidney disease (CKD) and renal transplant rejection are at high risk to develop advanced pathology including glomerular sclerosis and renal interstitial fibrosis. The elasticity of kidney tissues is associated with the disease progression and can be evaluated with ultrasound elastography. Understanding how tissue pathology changes the renal mechanical properties is crucial. Optical coherence elastography (OCE) might be a promising tool for evaluating renal tissues due to higher resolution. A phantom with 8% gelatin and 2% cellulose (50 mm) was fabricated to validate the ability of OCE to bulk materials and the results were confirmed by comparing the dataset obtained with an ultrasound-based Verasonics system as the ground truth. Excitation signals, composed with 4 cycles of a 400 Hz harmonic wave repeated at a rate of 38 Hz, were directly applied to the surface area with two directions and cortical regions of ex vivo porcine kidneys that had been cut open. Preliminary results showed that the velocity of surface wave on the cortical regions was near 1 m/s and corresponded with the result of shear waves from Verasonics system (1.2 m/s). Our study demonstrated that OCE has an ability to assess the mechanical properties of bulk materials and is a promising tool to evaluate mechanical properties of renal tissue with high resolution and sensitivity.

Abstract Motivation Functions of cancer driver genes vary substantially across tissues and organs. Distinguishing passenger genes, oncogenes (OGs) and tumor-suppressor genes (TSGs) for each cancer type is critical for understanding tumor biology and identifying clinically actionable targets. Although many computational tools are available to predict putative cancer driver genes, resources for context-aware classifications of OGs and TSGs are limited. Results We show that the direction and magnitude of somatic selection of protein-coding mutations are significantly different for passenger genes, OGs and TSGs. Based on these patterns, we develop a new method (genes under selection in tumors) to discover OGs and TSGs in a cancer-type specific manner. Genes under selection in tumors shows a high accuracy (92%) when evaluated via strict cross-validations. Its application to 10 172 tumor exomes found known and novel cancer drivers with high tissue-specificities. In 11 out of 13 OGs shared among multiple cancer types, we found functional domains selectively engaged in different cancers, suggesting differences in disease mechanisms. Availability and implementation An R implementation of the GUST algorithm is available at https://github.com/liliulab/gust. A database with pre-computed results is available at https://liliulab.shinyapps.io/gust. Supplementary information Supplementary data are available at Bioinformatics online.

Introduction Tissue loss as a consequence of congenital anomalies, trauma, malignancy, or gangrene represents a major health care problem in the United States. Because younger individuals are disproportionately affected, the costs are magnified over time and the resultant individual and societal effects are tremendous. The currently available options to restore soft tissue defects are associated with donor site morbidities. Vascularized composite allotransplantation may provide form, function, and esthetics without a donor site; however, it comes with the significant risk associated with toxic immunosuppression (Biomaterials. 2015;61:246-256, Ann Plast Surg. 2015;75(1):112-116, Transplantation. 2009;88(2):203-210). Engineered tissues offer promise in finding viable alternatives to allograft and autologous tissues. In this study, we present our simple and quick method to decellularize a muscle without disrupting the vascular network integrity or the extracellular matrix. Optimizing the decellularization process is a crucial step toward creating an “off-the-shelf” flap that can be used for soft tissue reconstruction. Methods The superficial gracilis muscle of 20 rats were harvested on their circulation and decellularized using perfusion with Krebs-Henseleit buffer and sodium dodecyl sulfate for 6 hours. These flaps were evaluated by gross morphology, histology, DNA quantification, integrity of the vascular network, scanning electron microscopy, and transmission electron microscopy. Results All samples were decellularized successfully as determined by DNA content and histological analysis for cellular content. The vascular network was preserved in all samples. Conclusions We present a quick, simple, and affordable method to decellularize a muscle flap through the vascular network. Our proposed method is efficient and can be completed in a significantly shorter time when compared with other methods. It is also safe and does not affect integrity of tissue, and this is essential for a reliable recellularization.

Abstract In glioblastoma (GBM), invasion and proliferation are reciprocally related—e.g., targeting one stimulates the other. Thus, effective therapy for GBM requires finding targets that drive both invasion and proliferation and which are druggable, ideally with FDA approved therapeutics. We find that the atypical protein kinase C isoform, PKCi meets these criteria. Using a human GBM tissue microarray, we find that PKCi protein expression fits a bimodal distribution, with >35% of GBMs showing high levels of PKCi expression. Genetic deletion of Prkci, the gene encoding mouse PKCi, impairs tumor invasion and proliferation both in vitro and in vivo, and significantly prolongs survival in an immunocompetent PDGF-driven orthotopic mouse model of GBM. PKCi can be selectively targeted with Auranofin, a small molecule PKCi inhibitor that has been FDA approved for treatment of inflammatory diseases. Like genetic deletion of Prkci Auranofin treatment significantly prolongs survival in our murine GBM model, and does so to a similar degree. Interestingly, analysis of a panel of human and murine GBM cells reveals that sensitivity to Auranofin inhibition of transformed growth directly correlates with expression of PKCi, indicating that PKCi expression profiling could serve as a predictive biomarker for responsiveness to Auranofin. However, genetically deleting or pharmacologically inactivating PKCi does not permanently arrest tumor growth, implying that GBM cells acquire mechanisms that allow them to compensate for the loss of this important signaling molecule. We are currently examining potential “escape” mechanisms through ‘omics-based approaches, which may enable us to enhance the therapeutic potential of Auranofin. Taken together, our results demonstrate that PKCi is a compelling therapeutic target for treatment of GBM that deserves further investigation.

Abstract Introduction Impaired plasminogen activation (PA) is causally related to the development of lung fibrosis. Prior studies demonstrate that enhanced PA in the lung limits the severity of scarring following injury and in vitro studies indicate that PA promotes matrix degradation and fibroblast apoptosis. These findings led us to hypothesize that increased PA in an in vivo model would enhance the resolution of established lung fibrosis in conjunction with increased myofibroblast apoptosis. Methods Transgenic C57BL/6 mice with doxycycline inducible lung-specific urokinase plasminogen activator (uPA) expression or littermate controls were treated (day 0) with bleomycin or saline. Doxycycline was initiated on days 1, 9, 14, or 21. Lung fibrosis, stiffness, apoptosis, epithelial barrier integrity, and inflammation were assessed. Results Protection from fibrosis with uPA upregulation from day 1 through day 28 was associated with reduced parenchymal stiffness as determined by atomic force microscopy. Initiation of uPA expression beginning in the late inflammatory or the early fibrotic phase reduced stiffness and fibrosis at day 28. Induction of uPA activity in mice with established fibrosis decreased lung collagen and lung stiffness while increasing myofibroblast apoptosis. Upregulation of uPA did not alter lung inflammation but was associated with improved epithelial cell homeostasis. Conclusion Restoring intrapulmonary PA activity diminishes lung fibrogenesis and enhances the resolution of established lung fibrosis. This PA-mediated resolution is associated with increased myofibroblast apoptosis and improved epithelial cell homeostasis. These studies support the potential capacity of the lung to resolve existing scar in murine models.

AbstractA current approach in bone tissue engineering is the implantation of polymeric scaffolds that promote osteoblast attachment and growth as well as biomineralization. One promising polymer is oligo[poly(ethylene glycol) fumarate] (OPF), a polyethylene glycol‐based material that is biocompatible, injectable, and biodegradable, but in its native form does not support robust bone cell attachment or growth. To address this issue, this study evaluated the osteoconductivity of bis[02‐(methacryloyloxy)ethyl] phosphate (BP) functionalized OPF hydrogels (OPF‐BP) using MC3T3‐E1 pre‐osteoblast cells, both before and after enzymatic mineralization with a calcium solution. The inclusion of negatively charged functional groups allowed for the tailored uptake and release of calcium, while also altering the mechanical properties and surface topography of the hydrogel surface. In cell culture, OPF‐BP hydrogels with 20 and 30% (w/w) BP optimized osteoblast attachment, proliferation, and differentiation after a 21‐day in vitro period. In addition, the OPF‐BP30 treatment, when mineralized with calcium, exhibited a 128% increase in osteocalcin expression when compared with the non‐mineralized treatment. These findings suggest that phosphate functionalization and enzymatic calcium mineralization can act synergistically to enhance the osteoconductivity of OPF hydrogels, making this processed material an attractive candidate for bone tissue engineering applications.

Abstract Background In patients with hemodynamically-significant chronic aortic valve regurgitation (AR), the prognostic significance of routinely-measured diastolic blood pressure (DBP), resting heart rate (RHR) and physical examination signs of heart failure (HF), is unknown. Purpose To investigate the association of DBP, RHR and HF signs, with all-cause mortality. Methods This retrospective cohort study included all consecutive patients with moderately-severe or severe AR within a tertiary-referral center from 2006–2017. Patients with ≥moderate aortic stenosis and those with ≥moderate mitral stenosis/regurgitation were excluded. Results Of 820 patients (age 59±17 years; 82% men) with DBP 64±13mmHg and RHR 64±12bpm, followed for 5.5±3.5 years, 104 died under medical management and 400 underwent aortic valve surgery (AVS). In multivariable analysis, DBP (adjusted-hazard ratio [HR] 0.82 [0.68–0.98] p=0.031, per 10mmHg increase), RHR (adjusted HR 1.2 [1.01–1.41] p=0.034 per 10bpm increase), and any HF signs (adjusted HR 1.66 [1.04–2.61] p=0.032) were associated with all-cause death independently of demographics, comorbidities, and guideline-derived surgical triggers. Mortality increased in a J-curve fashion for DBP starting at 70 mmHg and peaking at 55 mmHg (Fig A,C), and in a linear fashion for RHR starting at 60bpm (Fig B, D). The association persisted after additional adjustment for medications, presence of hypertension and time-dependent AVS. A clinical score combining DBP, RHR and any HF signs increased the mortality risk-discrimination of demographics and comorbidities from 74% to 79% (p=0.01), and from 79% to 82% after addition of surgical triggers (p=0.04). Figure. Risk of death by DBP and RHR Conclusions In patients with AR, routinely-measured vital signs and physical examination are strongly associated with all-cause mortality; lower DBP, higher RHR and any HF signs are independent predictors of mortality, and provide incremental mortality risk-discriminating value to baseline demographics, comorbidities and guideline-derived surgical triggers. These findings represent a clinical paradigm shift and have guideline implications.

We previously reported that testis‐specific Y‐encoded‐like protein (TSPYLs) are transcription regulators for CYP3A4, CYP2C9, and CYP2C19. Here, we observed dual roles for TSPYLs in mediating serotonin transport and the metabolism of selective serotonin reuptake inhibitors (SSRIs) in patients with major depressive disorder (MDD). The widely prescribed SSRIs, citalopram, and escitalopram are metabolized mainly by CYP2C19. The TSPYL1 rs3828743 single nucleotide polymorphism (SNP), which decreases its suppression of CYP2C19 expression, was associated with rapid escitalopram metabolism and worse treatment response in the Mayo PGRN‐AMPS clinical trial. We also found that TSPYLs can regulate expression of the serotonin transporter protein, SLC6A4, and, in turn, serotonin transport into cells. The SNPs in tight linkage disequilibrium with the TSPYL1 rs10223646 SNP were significantly correlated with baseline severity of depression in patients with MDD in the Sequenced Treatment Alternatives to Relieve Depression and International SSRI Pharmacogenomics Consortium clinical trials. Our findings suggest that genetic variation in TSPYL genes may be novel indicators for baseline severity of depression and SSRI poor response.